Download Ticks and tick-borne pathogens at the cutaneous interface: host

REVIEW ARTICLE
published: 19 November 2013
doi: 10.3389/fmicb.2013.00337
Ticks and tick-borne pathogens at the cutaneous interface:
host defenses, tick countermeasures, and a suitable
environment for pathogen establishment
Stephen Wikel*
Department of Medical Sciences, Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, CT, USA
Edited by:
Sukanya Narasimhan, Yale University
School of Medicine, USA
Reviewed by:
Amy J. Ullmann, Centers for Disease
Control and Prevention, USA
Jan Kopecky, University of South
Bohemia, Czech Republic
*Correspondence:
Stephen Wikel, Department of
Medical Sciences, Frank H. Netter
MD School of Medicine, Quinnipiac
University, 275 Mount Carmel
Avenue, MNH, Hamden, CT 06518,
USA
e-mail: stephen.wikel@quinnipiac.edu
Ticks are unique among hematophagous arthropods by continuous attachment to host
skin and blood feeding for days; complexity and diversity of biologically active molecules
differentially expressed in saliva of tick species; their ability to modulate the host defenses
of pain and itch, hemostasis, inflammation, innate and adaptive immunity, and wound
healing; and, the diverse array of infectious agents they transmit. All of these interactions
occur at the cutaneous interface in a complex sequence of carefully choreographed host
defense responses and tick countermeasures resulting in an environment that facilitates
successful blood feeding and establishment of tick-borne infectious agents within the
host. Here, we examine diverse patterns of tick attachment to host skin, blood feeding
mechanisms, salivary gland transcriptomes, bioactive molecules in tick saliva, timing
of pathogen transmission, and host responses to tick bite. Ticks engage and modulate
cutaneous and systemic immune defenses involving keratinocytes, natural killer cells,
dendritic cells, T cell subpopulations (Th1, Th2, Th17, Treg), B cells, neutrophils, mast cells,
basophils, endothelial cells, cytokines, chemokines, complement, and extracellular matrix.
A framework is proposed that integrates tick induced changes of skin immune effectors
with their ability to respond to tick-borne pathogens. Implications of these changes are
addressed. What are the consequences of tick modulation of host cutaneous defenses?
Does diversity of salivary gland transcriptomes determine differential modulation of host
inflammation and immune defenses and therefore, in part, the clades of pathogens
effectively transmitted by different tick species? Do ticks create an immunologically
modified cutaneous environment that enhances specific pathogen establishment? Can
tick saliva molecules be used to develop vaccines that block pathogen transmission?
Keywords: ticks, tick saliva, immune response, pathogen transmission, tick–host interface, immune modulation,
skin
INTRODUCTION
Complexity of tick–host–pathogen interactions is reflected in over
900 tick species; broad range of vertebrate host species from which
blood meals are successfully obtain, often by an individual tick
species; tick transmission of the greatest variety of infectious
agents of any blood feeding arthropod; increasing incidence and
geographic occurrence of tick-borne diseases; and, long durations
of host attachment, which require tick adaptations to cope with an
array of host defenses (Jongejan and Uilenberg, 2004; Dennis and
Piesman, 2005; Anderson and Magnarelli, 2008; Barker and Murrell, 2008; Brossard and Wikel, 2008; Randolph, 2010). Although
all ticks are pool feeders, variations among species occur in depth
of tick mouthpart penetration into host skin and production of
attachment cement (Moorhouse, 1969). Those variations detected
by histopathological studies of tick bite sites hinted at evolutionary variations in tick–host relationships, the vast scope of which
is now becoming widely appreciated as a result of characterization
of the salivary gland transcriptomes of many tick species (Ribeiro
and Francischetti, 2003). During the past 40 years, tick–host–
pathogen studies progressed remarkably from asking whether or
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not hosts developed adaptive immune responses to tick feeding
to currently defining the molecular and cell biological nature
of tick–host interactions (Willadsen, 1980; Wikel, 1982, 1996;
Ribeiro, 1995; Ribeiro et al., 2006; Steen et al., 2006; Brossard and
Wikel, 2008; Fontaine et al., 2011; Oliveira et al., 2011; Kazimirova
and Stibraniova, 2013). Research activity continues to increase as
indicated by a PubMed search of the term “tick salivary gland,”
which revealed seven manuscripts published during 1973; 53 published during 2010; and, 31 published during the first 8 months
of 2013.
TICK MODULATION OF THE HOST ENVIRONMENT: SCOPE
Blood feeding evolved along multiple times along independent
pathways among arthropods (Adams, 1999). Differences in duration of host interactions range from obtaining a blood meal within
minutes in the case of mosquitoes to continuous attachment to
the host for days in the case of ticks. Host defense mechanisms
of the skin are a threat to successful blood feeding that must
be counteracted. Arthropod saliva provides the answer to the
challenges posed by redundant host defense mechanisms of the
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Ticks and tick-borne pathogens at the cutaneous interface
skin (Ribeiro and Francischetti, 2003; Francischetti et al., 2009).
Tick saliva contains complex mixtures of molecules essential for
obtaining a blood meal that inhibit hemostasis; block pain and
itch responses that could alert an individual to the presence of
an attaching or feeding tick; modulate angiogenesis and extracellular matrix remodeling related to wound healing; and, act
as immunomodulators of innate and adaptive immunity (Wikel,
1996; Wikel and Bergman, 1997; Steen et al., 2006; Brossard and
Wikel, 2008; Oliveira et al., 2011; Mans, 2011; Stibraniova et al.,
2013). Tick saliva contains hundreds of different proteins that
are differentially expressed during blood feeding (Ribeiro et al.,
2006). Differences in salivary gland gene expression and saliva
composition exist across and within genera while some gene families are conserved across both argasid and ixodid families of ticks
(Alarcon-Chaidez et al., 2007; Mans et al., 2008; Francischetti et al.,
2009; Kazimirova and Stibraniova, 2013). Likewise, non-protein
molecules such as prostaglandin E2 and purine nucleoside adenosine are immunomodulatory molecules in tick saliva (Steen et al.,
2006; Oliveira et al., 2011).
Variations in tick salivary gland transcriptomes and saliva composition represent adaptations to physiological differences among
the broad range of vertebrate hosts and the continuous interplay between tick and host during blood feeding. Although host
defenses may share common features across species, differences
among host species likely result in evolutionary adaptations in
saliva molecules for specific tick–host relationships. Likewise, variations during blood feeding in expression of gene family members
would appear to be an effective strategy to reduce development
of host immunity to saliva molecules important, or essential, for
successful survival of the engorging tick. Depending upon tick
mouthpart structure among ixodid species, saliva may be injected
at the dermal–epidermal border or deep into the dermis (Moorhouse, 1969). Tick saliva is not simply injected into the skin in
a hypodermic needle and syringe manner. Immunofluorescent
microscopic examination of tick bite site skin biopsies revealed
saliva antigens trapped in attachment cement; in all layers of the
epidermis close to the site of tick attachment; and, at the dermal–
epidermal border some distance from the mouthparts, suggesting
the potential impact of saliva proteins over a wider area than might
be anticipated (Allen et al., 1979). Complexity of events at the
tick host interface is increased by the process in which injection
of saliva occurs alternatingly with uptake of blood as well as of
digested tissues at an increasing rate over the course of blood
feeding.
Skin has long been recognized as a physical barrier providing protection from injury and infection. As a first line of
defense, skin possesses an abundant population of cells and
molecular mediators of innate and adaptive immunity, resulting in what is recognized as the skin immune system (Kupper
and Fuhlbrigge, 2004; Nestle et al., 2009; Clark, 2010). Laceration of the skin immediately brings tick mouthparts into
contact with keratinocytes, which are important immune sentinels possessing receptors of the innate immune response, antimicrobial peptides, and pro-inflammatory cytokines (Martinon
et al., 2009; Nestle et al., 2009). The epidermis also contains important dendritic, antigen presenting, Langerhans cells (Merad et al.,
2008), which take up tick saliva antigens and transport them to
Frontiers in Microbiology | Microbial Immunology
draining lymph nodes (Allen et al., 1979; Nithiuthai and Allen,
1985).
As mouthparts are thrust into the dermis, saliva comes into
contact with nerve endings, blood and lymphatic vessels, fibroblasts, dendritic cells, macrophages, mast cells, natural killer (NK)
cells, effector, and numerous long lived memory T lymphocytes, and soluble mediators such as complement, cytokines,
chemokines, and lectins that contribute to local and systemic
immune responses (Kupper and Fuhlbrigge, 2004; Nestle et al.,
2009; Clark, 2010). Tick species developed multiple and diverse
countermeasures to circumvent many aspects of each of these
potential threats to increase their likelihood of successful host
attachment and blood feeding. Tick-borne infectious agents,
which themselves can modulate host immune defenses, are introduced into host skin where tick saliva reduced or modulated host
defenses, resulting in an environment potentially more favorable for pathogen establishment and development (Wikel, 1999;
Frischknecht, 2007).
Tick salivary gland gene expression profiles and saliva composition are topics of comprehensive reviews (Ribeiro and Francischetti, 2003; Steen et al., 2006; Anderson and Valenzuela, 2008;
Brossard and Wikel, 2008; Mans et al., 2008; Francischetti et al.,
2009; Fontaine et al., 2011; Mans, 2011; Oliveira et al., 2011;
Kazimirova and Stibraniova, 2013; Stibraniova et al., 2013). A
first line of defense is reducing the awareness of the attaching tick. Histamine and bradykinin are mediators of pain and
itch responses induced as a result of tissue injury (Alexander,
1986; Schmelz, 2002, 2010). Saliva of selected tick species contain
kininases (Ribeiro and Mather, 1998) and amine (histamine)binding lipocalins (Paesen et al., 2000) capable reducing pain and
itch responses, which could alert the host to the presence of an
attaching and feeding tick.
Inhibiting the complex mechanisms of hemostasis is crucial
to successful blood feeding and anti-hemostasis strategies evolved
by ticks include saliva vasodilators, inhibitors of platelet aggregation, and molecules that delay or inhibit components of the
coagulation cascade (Francischetti, 2010; Mans, 2011; Kazimirova
and Stibraniova, 2013). Tick saliva derived vasodilators include
non-protein prostaglandins (Ribeiro et al., 1992) and prostacyclin (Ribeiro et al., 1988). Tick saliva proteins contributing to
vasodilation are histamine releasing factor (Dai et al., 2010) of
Ixodes scapularis and a serine proteinase inhibitor (Chmelar et al.,
2012) of I. ricinus. Tick saliva modulation of the coagulation
cascade frequently focuses on factor Xa (Ibrahim et al., 2001;
Narasimhan et al., 2002), including factor Xa activation of factor V (Schuijt et al., 2013); contact phase inhibition (Decrem
et al., 2008); and, anti-thrombin activity (Koh and Kini, 2009).
Tick saliva acts in multiple ways to inhibit platelets by hydrolyzing ADP; inhibiting collagen activation of platelet receptors and
platelet aggregation; and, by its action on thrombin induced
platelet aggregation (Francischetti, 2010). A diagrammatic representation of the potential interactions of host hemostasis and
pain response pathways initiated by tick feeding is provided in
Steen et al. (2006). A description of anti-hemostasis strategies
across blood feeding arthropod families is provided with an excellent diagrammatic representation in the review by Fontaine et al.
(2011).
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Ticks and tick-borne pathogens at the cutaneous interface
Tick laceration of the skin, insertion of mouthparts, and creation of a “pool-like” feeding site in the dermis is an injury that
would initiate the complex synchronized events of wound repair
consisting of the immediate response, inflammation, proliferation,
migration, contraction, and migration phases (Shaw and Martin,
2009). Wound healing is a challenge to a tick which might need
to remain attached and obtain a blood meal for up to 2 weeks.
Phases of wound healing are an excellent example of the interconnected nature of the defenses of hemostasis, inflammation, and
immunity.
Hemostasis is an initial phase of wound healing, and as just
described, it is extensively modulated by a variety of tick countermeasures. Inflammatory phase of wound healing involves influx
and activation of neutrophils whose roles are to kill microbes and
contribute to remodeling of extracellular matrix, formation of
new blood vessels, and epithelia (Theilgaard-Monch et al., 2004).
Ticks modulate neutrophil attraction by modifying chemokine
and cytokine responses; reducing activation and down regulating reactive oxygen intermediates and nitric oxide; and, reducing
surface integrin expression as well as endothelium expression of
adhesion molecules (Brossard and Wikel, 2008; Kazimirova and
Stibraniova, 2013). Wound healing is also modulated by tick saliva
binding and inhibition of growth factors, reducing angiogenesis,
impairing fibroblast migration, and by the presence of metalloproteases that remodel extracellular matrix (Fukumoto et al., 2006;
Ribeiro et al., 2006; Kramer et al., 2008; Francischetti et al., 2009;
Islam et al., 2009; Kazimirova and Stibraniova, 2013). Saliva binding and inhibition of transforming growth factor-beta (TGF-β),
platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) reduces wound healing. These changes, when combined
with reduction in angiogenesis, contributes to reduced likelihood
of host rejection of the feeding tick.
Modulation of the inflammatory phase of wound healing by
saliva molecules of multiple tick species has broader implications
for impacting effector mechanisms of innate and adaptive immunity. Salivary gland extract of Dermacentor andersoni reduces
endothelial cell expression of intracellular adhesion molecule-1
(ICAM-1) and a similar extract prepared from partially fed I.
scapularis reduces vascular cell adhesion molecule-1 (VCAM-1)
and P-selection (Maxwell et al., 2005). Although different adhesion molecules are targeted by different tick species, outcomes
of potentially reducing leukocyte extravasation from the vascular
compartment to the bite site and for endothelial cell antigen presentation are similar. Inflammatory influx is further impaired by I.
scapularis saliva disintegrin metalloprotease-like saliva molecules,
which down-regulate β2 integrin adhesion molecule expression
on neutrophils (Guo et al., 2009). I. scapularis evolved saliva
adaptations to suppress both leukocyte and endothelial cell
molecules important in cell migration to sites of injury and
infection.
Development of host innate and acquired immune responses
to tick saliva components pose significant threats to an initial tick
infestation occurring for several days and to subsequent infestations throughout the life of a host. Repeated infestation of
guinea pigs and some cattle breeds with selected tick species
induces immune mediated resistance that significantly reduces the
number and blood meal volume of feeding ticks (Trager, 1939;
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Riek, 1962; Allen, 1973) while other tick–host associations do not
result in acquired resistance to infestation (Brossard and Wikel,
2008).
Repeated exposure to tick bites induces responses that reduce
pathogen transmission from tick to host. Rabbits infested with
pathogen-free D. andersoni adults were significantly resistant to
Francisella tularensis infection when subsequently infested with
infected D. andersoni nymphs (Bell et al., 1979). Co-feeding
transmission of Thogoto virus was reduced when infected ticks
were fed on tick resistant guinea pigs (Jones and Nuttall, 1990).
Repeated infestation with uninfected I. scapularis nymphs induced
resistance to subsequent transmission of Borrelia burgdorferi by
nymphs infesting guinea pigs expressing acquired resistant to tick
feeding (Nazario et al., 1998) or mice not resistant to tick feeding (Wikel et al., 1997). A survey of human subjects enrolled
in a 14-year study of Lyme disease risk in an endemic area
revealed that individuals who experienced cutaneous hypersensitivity, itch, to tick bite were significantly less likely to develop
B. burgdorferi infection (Burke et al., 2005). These studies suggest that tick feeding can induce host responses that diminish,
modify, and/or neutralize the actions of saliva molecules, which
may influence pathogen transmission. Potential contributing factors to this resistance are revealed by histological examination
of I. scapularis nymph attachment sites on mice receiving a
first infestation or a repeated infestation. Attachment site during an initial infestation contained very few inflammatory cells
at the bite site, while similar sites on mice infested 1 month
earlier and now receiving a second infestation, had a significant inflammatory infiltrate surrounding the tick mouthparts
(Krause et al., 2009). Skin biopsies of I. scapularis attachment sites
on tick infested people were histologically similar to those of
infested mice (Krause et al., 2009).
Innate and adaptive immune responses are particularly significant threats to successful blood feeding to which different tick
species developed broad and diverse arrays of immunomodulatory countermeasures (Gillespie et al., 2000; Valenzuela, 2004;
Steen et al., 2006; Brossard and Wikel, 2008; Fontaine et al., 2011;
Oliveira et al., 2011; Kazimirova and Stibraniova, 2013; Stibraniova et al., 2013). Diversity exists in regard to the capabilities
of individual tick species to modulate specific elements of host
immunity; however, collectively ticks evolutionarily developed
efficient strategies to counteract essentially all of the major categories of immune defenses. Modulation of host immunity is
especially essential for successful blood feeding, and as such
provides an environment that facilitates pathogen transmission,
establishment, and dissemination (Wikel, 1999; Brossard and
Wikel, 2008; Nuttall and Labuda, 2008; Hovius, 2009).
Alternative, lectin and classical pathways of complement activation are primary lines of defense against infectious agents with the
alternative and lectin pathways being integral to innate immune
defenses (Ricklin et al., 2010). Complement deposition occurs at
the dermal–epidermal junction of D. andersoni attachment sites
on previously infested hosts (Allen et al., 1979). The alternative
pathway is the most common target for tick modulation. Alternative pathway activation is an essential component for expression
of host acquired resistance to D. andersoni infestation (Wikel,
1979). I. scapularis saliva inhibits C3b deposition and release
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of the anaphylatoxin C3a, which possesses both vasoactive and
chemotactic activities (Ribeiro and Spielman, 1986; Ribeiro, 1987).
Salivary gland extracts of I. ricinus, I. hexagonus, and I. uriae each
inhibited alternative pathway activation in sera of natural host
species (Lawrie et al., 1999). I. scapularis saliva dissociates factor
Bb from C3b in the alternative pathway C3 convertase (Valenzuela et al., 2000; Tyson et al., 2007). I. ricinus saliva also inhibits
alternative pathway activation (Daix et al., 2007) and binds factor
P, whose function is to stabilize the alternative pathway C3 convertase (Couvreur et al., 2008). Blocking factor P binding allows
complement regulatory proteins to displace C3b from factor Bb
and cleave C3b, thus reducing alternative pathway activity. Salivary glands extract of the argasid tick, Ornithodoros moubata,
inhibits C5a production from cleavage of C5 by both classical and
alternative C5 convertases, inhibiting molecular assembly of the
late steps of complement activation (Nunn et al., 2005). Targeted
inhibition of the alternative pathway has significant implications for survival of tick-borne infectious agents deposited at the
bite site.
Natural killer cells are innate immune response effectors capable of killing certain types of tumor cells and microbes; however,
NK cells also function as regulatory cells in interactions with
endothelial cells, dendritic cells, macrophages, and T lymphocytes (Vivier et al., 2008). Down-regulating the action of NK
cells, while reducing an anti-microbial defense, would potentially
reduce inflammation and impact the ability of the innate immune
response to skew the subsequent adaptive immune response
along a specific pathway. Salivary gland extracts prepared from
Dermacentor reticulatus, Amblyomma variegatum, Haemaphysalis
inermis, and I. ricinus each independently, moderately suppressed
target cell killing (Kubes et al., 1994, 2002; Kopecky and Kuthejlova,
1998).
Neutrophils are the first wave of the innate immune response
to injury and infection, and they occur in inflammatory infiltrates at tick attachment sites (Theis and Budwiser, 1974; Krause
et al., 2009). As described for modulation of host wound healing, migration of neutrophils, and other leukocytes migration
into tissues at tick attachment sites is modified by alteration of
expression of adhesion molecule and their ligands on endothelial
cells and leukocytes (Maxwell et al., 2005; Guo et al., 2009). Saliva
of I. scapularis inhibits neutrophil phagocytosis and superoxide
anion mediated killing (Ribeiro et al., 1990), and an I. ricinus salivary gland lipocalin reduces neutrophil activation and chemotaxis
(Beaufays et al., 2008). Multiple tick species synthesize salivary
gland inhibitors for the neutrophil chemoattractant interleukin-8
(IL-8, also known as CXCL8) and other chemokines (Hajnická
et al., 2001; Vancová et al., 2010).
Through their role in orchestrating immune responses, skin
dendritic cell subpopulations are a vital link between innate and
adaptive immunity (Nestle et al., 2009), which makes them logical cell populations to be modulated by tick saliva. Epidermal
Langerhans cells are dendritic cells (Merad et al., 2008) that trap
tick saliva antigens and transport them to draining lymph nodes
for presentation to T lymphocytes (Allen et al., 1979; Nithiuthai
and Allen, 1985). Langerhans cells induce CD4+ lymphocyte differentiation to Th2 effector lymphocytes (Hunger et al., 2004).
Many tick species preferentially induce host Th2 lymphocyte
Frontiers in Microbiology | Microbial Immunology
responses, which are thought to down regulate pro-inflammatory
cytokines (Brossard and Wikel, 2008). Different immunomodulatory strategies are employed by different tick species. Rhipicephalus
sanguineus saliva inhibits dendritic cell differentiation (Cavassani
et al., 2005); reduces expression of chemokine receptor and migration in response to chemoattractants (Oliveira et al., 2008) and,
increases production of interleukin-10 (Oliveira et al., 2010). I.
scapularis saliva inhibits dendritic cell cytokine elaboration and
expression of the co-stimulatory molecule CD40, resulting in
reduced stimulation of CD4+ T lymphocytes (Sá-Nunes et al.,
2007). Rhipicephalus appendiculatus saliva protein inhibits dendritic cell up-regulation of co-stimulatory molecule CD86 and
maturation marker CD83; reduces secretion of the cytokines
interferon-α (INF-α), interferon-γ (INF-γ), IL-1, IL-6, IL-12,
and TNF-α; and, thus diminishes Th1 and Th17 polarizing ability of human monocyte derived dendritic cells (Preston et al.,
2013).
Selected tick host relationships are characterized by basophil
rich accumulations at tick attachment sites upon repeated infestation (Allen, 1973; Allen et al., 1977). Basophils have a nonredundant role in acquired resistance to Haemophysalis longicornis
(Wada et al., 2010). Interestingly, basophils can act as antigen
presenting cells, and they skew CD4+ T lymphocyte responses
to a Th2 profile (Sokol and Medzhitov, 2010). Tick feeding
preferentially induces Th2 polarization (Brossard and Wikel,
2008).
Cytokines are involved in nearly every aspect of immune regulation and effector function, and they represent a natural communication bridge between innate and adaptive immunity (Dinarello,
2007). Collectively, cytokines include interleukins, interferons,
tumor necrosis factor, and chemokines. Many cytokines possess
redundant and overlapping biological activities, including proinflammatory, anti-inflammatory, and immunoregulatory roles.
In order to be successful blood feeding ectoparasites, diverse
tick species developed mechanisms to modulate host interleukins,
interferons, tumor necrosis factor, and chemokines; to suppress inflammatory responses; and, to deviate host T lymphocyte
responses to profiles that are potentially less damaging to the
feeding tick (Ramachandra and Wikel, 1992; Brossard and Wikel,
2008; Fontaine et al., 2011; Oliveira et al., 2011; Kazimirova and
Stibraniova, 2013).
Tumor necrosis factor-α is a pro-inflammatory cytokine suppressed by salivary gland molecules of D. andersoni (Ramachandra
and Wikel, 1992), I. ricinus (Pechová et al., 2004), I. scapularis (Hovius et al., 2008a), and Hyalomma asiaticum asiaticum
(Wu et al., 2010). Simultaneous with suppression of TNF-α, D.
andersoni salivary gland extract suppresses elaboration of the proinflammatory cytokines, IL-1 (Ramachandra and Wikel, 1992),
IFN-γ (Prevot et al., 2009; Wu et al., 2010) accompanied by
up-regulation of IL-10, which down-regulates Th1 cytokines,
expression of MHC class II molecules, and macrophage costimulatory molecules (Pestka et al., 2004; Wu et al., 2010). Further
tick modulation of cytokines occurs in the context of adaptive
immune response modulation.
Chemokines are chemoattractant proteins with multiple, often
redundant, roles in inflammatory and immune responses related
to their elaboration and interactions with chemokine receptors
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that are differentially expressed on a variety of cell types (Sallusto
and Baggiolini, 2008). Chemokine expression by endothelium
and interaction with chemokine receptors on leukocytes modifies adhesion molecule interactions that facilitate extravasation of
leukocytes across the vascular endothelium into tissues as well
as activation at sites of injury and infection. Selective homing
and localization of specific subpopulations of T lymphocytes to
the skin are controlled by orchestrated, sequential, and integrated
interactions of distinct sets of chemokines and adhesion molecules
(Campbell et al., 1999; Sallusto and Baggiolini, 2008).
Tick modulation of chemokines, adhesion molecules, and
pro-inflammatory cytokines constitutes an effective multi-faceted
approach to down-regulation of host innate and adaptive immune
responses that could negatively impact tick blood feeding success. Multiple chemokine inhibitory activities are associated with
the saliva of numerous tick species (Brossard and Wikel, 2008;
Kazimirova and Stibraniova, 2013). Salivary glands of A. variegatum, R. appendiculatus, and R. sanguineus contain inhibitors
of the chemokine CCL3, which attracts neutrophils, monocytes,
eosinophils, basophils, NK cells, and T lymphocytes (Vancová
et al., 2007; Deruaz et al., 2008; Oliveira et al., 2008; Peterkova et al.,
2008). Other chemokines blocked by tick salivary gland molecules
include the neutrophil chemokine CXCL8 (IL-8); monocyte
attractant CCL2; CCL4 attractant for monocytes and NK cells;
CCL5 attractant for basophils, eosinophils, and T lymphocytes;
CCL11 attractant for eosinophils; CCL18 attracting T lymphocytes; and, CXCL1 attracting neutrophils (Vancová et al., 2007;
Deruaz et al., 2008; Oliveira et al., 2008; Peterkova et al., 2008).
Tick anti-chemokine activities represent the evolution of saliva
molecules that modulate multiple and redundant chemokine
pathways.
Adaptive immune response modulation by ticks is achieved
through the direct action of saliva molecules on B and T lymphocytes as well as through saliva induced changes on dendritic
and other antigen presenting cells, and soluble mediators of the
immune response (Ribeiro, 1995; Wikel, 1996; Gillespie et al.,
2000; Steen et al., 2006; Brossard and Wikel, 2008; Oliveira et al.,
2011; Fontaine et al., 2011; Kazimirova and Stibraniova, 2013;
Stibraniova et al., 2013). Using a bioassay of cytokine function, T
lymphocyte elaboration of the growth factor interleukin-2 (IL-2)
was suppressed by D. andersoni salivary gland extract (Ramachandra and Wikel, 1992). An IL-2 binding protein was isolated from
the salivary glands of I. scapularis (Gillespie et al., 2001). A commonly observed theme for numerous tick–host associations is
infestation induced down regulation of the Th1 cytokines, IL-2
and IFN-γ, and up-regulation of the Th2 cytokine, IL-4, IL5, IL-6, and IL-10 (Schoeler and Wikel, 2001; Brossard and
Wikel, 2008; Kazimirova and Stibraniova, 2013). A novel 39.7 kDa
sphingomyelinase-like protein cloned from an I. scapularis salivary
gland cDNA library was the first tick protein shown to program
host CD4+ T lymphocytes to express IL-4 (Alarcon-Chaidez et al.,
2009).
Tick salivary gland molecules also inhibit T lymphocyte proliferation (Brossard and Wikel, 2008; Kazimirova and Stibraniova,
2013). A 36 kDa protein occurring in D. andersoni female and
male saliva suppressed T lymphocyte proliferation (Bergman et al.,
2000). A protein secreted by I. ricinus salivary glands suppresses
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T lymphocyte proliferation, induces a Th2 cytokine profile, and
inhibits macrophage pro-inflammatory cytokines (Leboulle et al.,
2002). The I. scapularis saliva protein, Salp15, inhibits IL-2 elaboration, CD4+ T lymphocyte proliferation, and T lymphocyte
receptor intracellular signaling pathways (Juncadella and Anguita,
2009). Molecules similar to Salp15 likely occur widely in the
genus Ixodes since homologues were found in the salivary glands
of I. ricinus (Hovius et al., 2007), I. pacificus and I. persulcatus
(Hojgaard et al., 2009). An I. scapularis saliva cystatin inhibited
cytotoxic T lymphocyte proliferation in vitro and reduced an
in vivo carrageenan induced inflammatory response (Kotsyfakis
et al., 2006).
The Th17 lineage of CD4+ T lymphocytes are potent inducers of inflammatory responses (Korn et al., 2009). Transcriptional
profiling of host I. scapularis attachment sites during initial
and second infestations revealed an inhibition of Th17 immune
responsiveness (Heinze et al., 2012). A gene encoding a salivary
protein of R. appendiculatus was cloned, expressed, and the recombinant protein found to inhibit Th17 polarization (Preston et al.,
2013). Concurrently with Th17 down-regulation, increased activity was observed for transcripts associated with regulatory T
lymphocyte activity, IL-10, and suppressors of cytokine signaling
molecules (Heinze et al., 2012).
TICK MODULATION OF THE HOST ENVIRONMENT:
IMPLICATIONS
The array of diverse strategies evolved by different tick species
to modulate multiple, interconnected host defense pathways converge as a common outcome of providing an environment that
favors tick feeding success and in turn provides an immunologically modified environment for establishment and dissemination
of tick-borne infectious agents. Complexity of the co-evolution of
ticks, tick-borne pathogens, and host defenses is just beginning to
be dissected at the cell biological and molecular levels in combination with identification of tick saliva molecules responsible for
modifying or driving many of these events. An amazing, orchestrated web of diverse interactions is being defined in this highly
fertile research area.
Tick salivary gland molecules enhance transmission and establishment of Thogoto virus (Jones et al., 1989) and Theileria parva
(Shaw et al., 1993) by R. appendiculatus; tick-borne encephalitis
virus (Labuda et al., 1993) and F. tularensis (Krocova et al., 2003)
by I. ricinus; vesicular stomatitis virus by D. reticulatus (Hajnická
et al., 2000); and, Borrelia burgdorfei by I. scapularis (Zeidner et al.,
2002) and by I. ricinus (Machackova et al., 2006; Horka et al.,
2009). Influence of tick factors on the host response to Borrelia infection is demonstrated in development of a Th2 response
component to I. ricinus transmission compared to a mixed Th1
and Th2 response following needle inoculation of 2 × 103 spirochetes intradermally (Christe et al., 2000). I. scapularis infestation
polarizes host cytokine responses to a Th2 profile and suppresses
pro-inflammatory cytokines (Schoeler et al., 1999; Brossard and
Wikel, 2008). Passively restoring pro-inflammatory (TNF-α) and
Th1 (IL-2, IFN-γ) lymphocyte cytokines reduced by tick feeding,
significantly enhances resistance to I. scapularis transmission of
B. burgdorferi (Zeidner et al., 1996). Tick salivary gland molecules
efficiently reduce inflammatory infiltrates at tick attachment sites
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Ticks and tick-borne pathogens at the cutaneous interface
by multiple mechanisms. Inoculation of I. ricinus saliva with Borrelia garinii spirochetes results in a reduced inflammatory response
and number of cells accumulating in draining lymph nodes (Severinová, 2005; Kern et al., 2011). Suggestion of reduced cellular
traffic from the bite site naturally leads to the impact of I. ricinus
saliva molecules on dendritic cells and their reduced ability to optimally present Borrelia antigens (Slamova et al., 2011; Lieskovska
and Kopecky, 2012). Immunoglobulin response to B. burgdorferi
outer surface protein C (OspC) is reduced by a B lymphocyte
inhibitory I. ricinus inhibitory protein (Hannier et al., 2003). Protection of Borrelia from antibody is also attributed to the action
of I scapularis Salp15 and its I. ricinus homologue (Hovius et al.,
2008b). Additional Salp proteins contribute to protection and
transmission of Borrelia (Kazimirova and Stibraniova, 2013).
The relationship amongst tick, Lyme borreliosis spirochetes,
and host complement is an intriguing example of co-evolutionary
adaptations. I. scapularis and I. ricinus saliva inhibit alternative
pathway C3 convertase activity by causing dissociation of C3b
from Bb (Valenzuela et al., 2000; Daix et al., 2007; Tyson et al.,
2007). Tick salivary lectin pathway inhibitor (TSPLI) present in
saliva of I. scapularis reduces spirochete killing by inhibiting lectin
pathway complement mediated activation on the surface of B.
burgdorferi (Schuijt et al., 2011). In concert with tick modulation
of host complement defenses, B. burgdorferi itself inhibits innate
immune defenses, including complement activation (Singh and
Girschick, 2004; Hovius, 2009). Borrelia burgdorferi binds complement regulator acquiring proteins that facilitate binding of factor
H and factor H-like regulator molecules that inhibit C3b (Hellwage et al., 2001; Kraiczy et al., 2001; Stevenson et al., 2002). A
recent review describes B. burgdorferi complement evasion strategies involving host regulatory proteins; spirochete production of
membrane-bound mimics to prevent complement activation; and,
use of tick proteins (de Taeye et al., 2013). The impact of tick modulation of the host environment is all the more striking since peak
transmission of spirochetes doses not occur until approximately
48 h of blood feeding by I. scapularis nymphs (des Vignes et al.,
2001). A different impact of tick modulation of the host environment is anticipated for tick-borne encephalitis virus, which
is transmitted within minutes of the initiation of blood feeding
(Alekseev and Chunikhin, 1990).
Murine bone marrow derived macrophages exposed to I. scapularis saliva during stimulation with Anaplasma phagocytophilum
display reduced elaboration of IL-1β, TNF-α, IL-6, and IL-12p40
(Chen et al., 2012). I. scapularis saliva inhibits pro-inflammatory
cytokines through both Toll-like and Nod-like signaling pathways.
Likewise, TNF-α stimulated peripheral blood mononuclear cells
were diminished in their ability to secret IL-8 when cultured in
the presence of I. scapularis saliva (Chen et al., 2012). As an interesting example of tick and tick-borne pathogen co-adaptation,
A. phagocytophilum infection induces up-regulation of α1, 3fucosyltransferases in I. scapularis to increase tick cold hardiness
(Neelakanta et al., 2010).
CONCLUSION
Based upon findings reported in the literature to date, there
exists an increasing body of data that links tick manipulation of
host defenses with those strategies used and/or beneficial to the
Frontiers in Microbiology | Microbial Immunology
infectious agents transmitted to avoid host immunity. Tick manipulation of host defenses is one element in determining the clade
of pathogens transmitted successfully by a specific tick species.
Tick innate immune defenses are also critical factors in determining tick vector competence, and fortunately the availability
of genome data and functional genomics tools are providing new
insights into understanding these important components of tick
vector biology (Hajdusek et al., 2013). A productive avenue of
investigation will be blending studies that investigate the interrelationship among a tick transmitted infectious agent; tick innate
immunity and barriers for pathogen development; tick modulation of host defenses; and, pathogen modulation of host
defenses.
Development of tick vector blocking vaccines to prevent transmission of multiple different pathogens transmitted is a potentially
feasible control strategy. However, achieving a vaccine that is
highly effective for human use will likely require multiple antigens that target saliva molecules that act in an integrated manner
to provide protection. The task of antigen identification, optimal
formulation, and delivery will be complicated (Willadsen, 2008).
Saliva molecules implicated in potentiating pathogen transmission are potential vaccine candidate immunogens (Ramamoorthi
et al., 2005; Dai et al., 2010; Kotsyfakis et al., 2010; Schuijt et al.,
2011).
Significant progress is being made in characterizing tick manipulations of host defense; the inter-relatedness of those modification to enhance tick feeding success; and, the implications of those
changes for successful pathogen transmission and establishment
in the host. A potentially highly productive approach to dissection
of the complex interrelationships of tick, host, and tick-borne
pathogen over the course of tick blood feeding would be to institute a systems biology approach to the characterization of gene
expression in all three components of this dynamic and important
relationship. The tools for molecular analysis and the computational power are at hand. In addition to gaining fundamental
understanding of the relationship of tick, host and pathogen,
novel control strategies for tick-borne diseases will almost certainly
emerge.
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Conflict of Interest Statement: The author declares that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 10 September 2013; paper pending published: 23 September 2013; accepted:
25 October 2013; published online: 19 November 2013.
Citation: Wikel S (2013) Ticks and tick-borne pathogens at the cutaneous interface: host
defenses, tick countermeasures, and a suitable environment for pathogen establishment.
Front. Microbiol. 4:337. doi: 10.3389/fmicb.2013.00337
This article was submitted to Microbial Immunology, a section of the journal Frontiers
in Microbiology.
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